PROJECT SUMMARY Tuberculosis (TB) is a global epidemic responsible for 9 million new cases and 1.5 million deaths annually. It is also the most common contagious infection in HIV-immunocompromised patients leading to death. It is now well established that spread of TB is principally facilitated by pulmonary cavitation with cough-generated aerosol. Cavitation is a classic feature of active TB. It is the site of high bacterial burden, and is associated with treatment failure and drug resistance. It occurs as a result of incompletely understood mechanisms whereby the infection, originally confined within granulomas, leads to extensive caseous necrosis and tissue destruction. Elucidating pathways relevant to lung tissue destruction and remodeling might therefore lead to strategies that target disease transmission. Using a reliable cavitary model of TB in rabbits, and novel CT scanning and imaging techniques, we recently showed that matrix-degrading enzymes involved in tissue remodeling are essential for progression of dense consolidated lesions that lead to cavitation. In a rabbit model of TB, we found increased transcripts of matrix metalloproteinases MMP-1, 3,7, 12 and 13, and increased cathepsin K (CTSK), associated with granulomatous and cavitary pathologies. We also found elevated MMPs and CTSK in patients with active pulmonary TB. Based on our studies, we hypothesize that extracellular matrix degrading activity promotes TB pathology. To test this hypothesis, in this exploratory study, we propose to evaluate the effects of inhibitors of collagenases and CTSK, currently in preclinical and clinical trials, in cavity formation and progression of TB using animal model of cavitary disease. In aim 1, we will evaluate the efficacy of selective MMP inhibitor Ro32-3555 in reducing lung pathology in a rabbit cavitary model of TB. End point analysis will include histology, bacterial counts, lung pathology, protease activity and quantitation of matrix degradation. In aim 2, we will evaluate the efficacy of selective CTSK inhibitor odanacatib in the rabbit cavitation model. Both drugs will be tested in early and late intervention protocols to evaluate if they either prevent the formation of cavities, or lead to resolution of established cavitary lesions, or both.